The present invention relates to a method for controlling a freeze-drying process. It finds particular application in processes in which a frozen product is arranged on temperature adjustable surfaces in an air-evacuated chamber that is first subject to a main drying phase and subsequently to an after-drying phase. During the main drying phase, the temperature of ice enclosed in the product to be dried is continuously measured. The chamber pressure and/or the temperature of the storage surfaces are modified during a transition from the main drying phase to an after-drying phase.
Freeze-drying is a method for removal of water from a water-containing frozen product, for example from pharmaceutical products or food items. In general, the process is performed at an air pressure which is low vis-a-vis the water vapor pressure at the selected temperature of the ice. For example, an ice temperature of -20.degree. C. corresponds to a water vapor pressure (in equilibrium) of 1.03 mbar. In order for the water vapor to be able to flow from the surface of the ice into the drying chamber, the water vapor pressure in the drying chamber must clearly be lower than 1.03 mbar, e.g., 0.4 mbar. Thus, it is appropriate to select relative to said pressure value a low pressure, for example, 0.05 mbar. Freeze-drying is normally done in a chamber in which temperable storage surfaces are located with an attached evacuation device, for example, an ice condenser combined with a vacuum pump.
Basically, two drying phases are characteristic for the course of the drying process. As long as there is still crystallized (frozen) water within the product, said drying phase is called main or sublimation drying. If the shut-off device between the chamber and the evacuation device is cut off for only a brief period of time (a few seconds) during this drying phase, equilibrium water vapor pressure becomes established inside the chamber which corresponds to the prevailing temperature of the ice.
From the rise in pressure, a direct conclusion can be drawn with respect to the temperature of the ice. Said method for measuring the ice temperature is known under the concept of barometric temperature measuring and is described, for example, in DE-PS 10 38 988.
As long as solid ice is present in the product, i.e., during the main drying phase, the temperature of the product must not rise above certain values, ranging, in most cases, far below 0.degree. C. in order to avoid impairment of the quality and/or the properties of the product. With progressing drying, the ice nuclei present in the product continue to decrease. In the area of dry marginal zones, higher temperatures are already permissible.
When water is no longer present in the form of ice, the remaining water has been absorbed by the dry product or more or less firmly bonded thereto as well. Removal of this remaining water takes place during the after-drying or desorption drying phase. The quantity of water which can be desorbed during this phase depends upon the temperature of the product, the type of water bonding, and the quality of the still present water. The after-drying phase is initiated by another modification in the physical conditions governing the course of the drying process.
A method of the initially mentioned type is known from the reference DE-PS 10 38 988. For determining the transition from the main drying phase to the after-drying phase, measurements are taken by means that also serve to measure the temperature of the ice. To that end, the shut-off times, which last only a few seconds when measuring the temperature of the ice, are substantially lengthened, i.e., to two minutes or longer.
If, after shut-off times of this magnitude, there occurs an almost constant difference between the operating pressure and the saturation vapor pressure, it may be assumed that the solid ice has been completely removed from the product and that the main drying phase is, in fact, completed. The storage surface temperature and the pressure can be adjusted to the particular values at which the after-drying phase is there to take place.
The substantial lengthening of the shut-off time is a disadvantage with respect to the described method. If the main drying phase has not been completed as yet, there is the danger than an extension of the shut-off time will result in a no longer permissible temperature increase of the ice-containing product and thus lead to its destruction. In modern freeze-drying plants of the pharmaceutical industry, the value of one batch is frequently over $600,000. Therefore, it is important to avoid product endangerment.
The present application proposes a method for controlling a freeze-drying process of the initially mentioned type, wherein the drawback of longer shut-off times between chamber and evacuation device are not necessary.
The modifications in the pressure and/or the storage surface temperature, characterizing the transition from the main drying phase of the after-drying phase, are carried out subject to changes in the ice temperature. This process makes use of the phenomenon that the values of the ice temperature measured during the main drying phase become smaller during the transition from main drying to after-drying. Obviously, the only apparent modification of the ice temperature is, in fact, minor, but can be accurately determined with the aid of modern computers. Since measurements of only the ice temperature are taken during brief shut-off times, the danger of product-thawing is avoided.
During the main drying phase, the ice nuclei present in the product, become smaller and smaller. In many instances, following the formation of dry marginal zones, there exists the possibility of already increasing the temperature of the storage surfaces during the main drying phase without endangering the quality of the product. Modification of the drying conditions of this type can also be made according to the invention in dependence on modifications of the ice temperature.
The ice temperature values measured during the main drying phase changed very little. Therefore, it is appropriate to average the measured values of the ice temperature with the preceding measured values and, in order to determine a given change in the temperature of the ice, to continuously compare the highest of the ascertained ice temperature averages with the respective actual values of the ice temperature. Changes in ice temperature by 1.2.degree. C. or 3.degree. C., for example, can clearly be ascertained according to this process.
Measurement-taking of the ice temperature itself is appropriately done according to the initially mentioned barometric temperature measuring, i.e., a conclusion is drawn as to the temperature of the ice from the rise in the pressure of the chamber, which occurs after the isolation of the chamber from its evacuation device. In order to keep the shut-off times as short as possible in accordance with a general aim of the invention, the following procedure is suggested. After shutting off the chamber from the evacuation device, the rising chamber pressure is continuously measured 10 to 100 times per second. These measured values are entered into a computer. The values measured in the first seconds of the rise in pressure produce an S-shaped curve, i.e., a curve with a turning point. With the aid of the computer, said curve is continuously differentiated, in other words, the temporary modification of the pressure (dp/dt) is being monitored. The measurement-taking of the rise in pressure, needed for sufficiently precise determination of the ice temperature, may be interrupted when the pressure increase curve has reached its turning point, in other words, when the first derivative of said curve has reached its maximum. At that moment it is possible, therefore, to terminate the shut-off time and to re-establish the connection between the chamber and the evacuation device. This prevents the ice temperature from being surpassed.
The continuous, short-term and relatively precise determination of the ice temperature permits very early ascertainment of ice temperature fluctuations which exceed the measuring accuracy. If fluctuations in the chamber pressure or the storage surface temperature are excluded, then fluctuations in the temperature of the ice are an indication of an incongruity in the ice structure. Thermal conductance and water vapor transport differ in zones with very small or aggregated large crystals. This also applies with respect to products collapsed during the main drying phase, since at that point in time, water instead of ice is present in several zones. Fluctuations in the temperature of the ice may thus indicate errors during freezing of the product or storage surface temperatures which are too high.